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The aim of this paper is to explore high school students' critical consciousness development in the context of youth participatory action research (YPAR) focused on food security at an alternative school in Alabama. The YPAR project took place in an elective agriscience class with 10 students (Seven Black, two white, one Latino) who were in the 10th to 12th grades. Utilizing data from researcher notes, classroom observations, and archival classroom documents, we present students' YPAR project outcomes to share their research-driven solutions to food insecurity in their community. Vignettes of classroom dialogue are also constructed to illustrate moments of reflection in the YPAR context about food security. We present three "critical moments," or instances of social analysis, to illustrate how students' individual-level attributions occurred alongside teacher dialogue and student-led investigation of structural inequities in the community. Findings illustrate how students' nonlinear critical consciousness development consisted of reliance on individual-level attributions in classroom dialogue co-occurring with systems-thinking activities and other YPAR project outcomes. This paper has implications for research on the imperfect and wavering nature of adolescent critical consciousness development in YPAR.

Abstract Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson’s disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4–5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

Abstract Inflammasome formation, arising from pathogen or internal activating signals, is a key step in canonical pyroptosis, a gasdermin-mediated inflammatory cell death. Inhibition of pyroptosis has great clinical relevance due to its involvement in many different disease states. Current inhibitors of pyroptosis either only inhibit the final lytic step, which still allows inflammatory signal release, or only inhibit a single inflammasome, which does not account for inherent redundancy in activation of other inflammatory pathways. Here, we show that thiomuscimol, a structural analog of the lysis inhibitor muscimol, exhibits unique inhibitory activity upstream of plasma membrane rupture. We find that thiomuscimol inhibits inflammasome formation, as well as downstream caspase-1 activation, initiated by multiple pyroptotic signals, regardless of whether NLR recruitment of caspase-1 to the inflammasome relies on the ASC adapter protein. The ability of thiomuscimol to block multiple different inflammasomes opens the door for development of therapeutics with increased applications to broadly inhibit pyroptosis in multiple pathological settings.

Abstract Spinal cord injury creates an inflammatory microenvironment that regulates the capacity of transplanted human Neural Stem Cells (hNSC) to migrate, differentiate, and repair injury. Despite similarities in gene expression and markers detected by immunostaining, hNSC populations exhibit heterogeneous therapeutic potential. This heterogeneity derives in part from the epigenetic landscape in the hNSC genome, specifically methylation (5mC) and hydroxymethylation (5hmC) state, which may affect the response of transplanted hNSC in the injury microenvironment and thereby modulate repair capacity. We demonstrate a significant up-regulation of methylcytosine dioxygenase 2 gene (TET2) expression in undifferentiated hNSC derived from human embryonic stem cells (hES-NSC), and report that this is associated with hES-NSC competence for differentiation marker expression. TET2 protein catalyzes active demethylation and TET2 upregulation could be a signature of pluripotent exit, while shaping the epigenetic landscape in hES-NSC. We determine that the inflammatory environment overrides epigenetic programming in vitro and in vivo by directly modulating TET2 expression levels in hES-NSC to change cell fate. We also report the effect of cell fate and microenvironment on differential methylation 5mC/5hmC balance. Understanding how the activity of epigenetic modifiers changes within the transplantation niche in vivo is crucial for assessment of hES-NSC behavior for potential clinical applications.

In a population-based birth cohort study of respiratory syncytial virus surveillance in the United States, 897/1,680 (53.4%) children were infected during infancy; 25 (2.8%) of those were hospitalized. Among symptomatic infants, 143/324 (44.1%) had lower respiratory tract infections. These data provide benchmarks to monitor effects of maternal vaccines and extended half-life monoclonal antibodies.

Objective: To examine the influence of dynamic and trending descriptive norms on increasing physical activity and decreasing the sedentary behaviors of university students while on campus. Participants: One-hundred fifty-six university students from a Canadian university completed this study. Methods: Participants were randomly assigned to receive one of four online messages containing normative information about the on-campus behavior of university students. On-campus physical activity and sedentary behavior were measured pre- and post-message. Results: The results revealed that students exposed to the trending norm reported a greater decrease in sedentary behavior than students in the control condition, p = 0.007. Conclusion: Results provide preliminary experimental evidence that trending norm messages may serve to decrease the sedentary behavior of students while on campus.

The success of teachers is tied to their effectiveness in managing student behavior. In this meta-analysis, we identified 49 single-case-design studies that evaluated the effectiveness of teacher training on their implementation of behavioral support strategies. Training was most often provided in a one-on-one format (n = 18) and included ongoing coaching (n = 20). Thirty-three of the 49 designs met What Works Clearinghouse standards with or without reservations. The overall between-case standardized mean difference effect size was d = 1.50. We analyzed and grouped teacher- and student-level outcomes as a result of training into five domains: (a) teacher-delivered praise (d = 1.94), (b) teacher desirable behavior (e.g., treatment fidelity; d = 1.22), (c) teacher undesirable behavior (e.g., reprimands; d = 0.87), (d) student desirable behavior (d = 1.88), and (e) student undesirable behavior (d = 1.22). Across all studies, the combined nonoverlap of all pairs scores ranged from 0.37 to 1.0 (M = 0.866). We discuss future areas of research as well as implications for teacher training in behavioral support implementation.

Background: Increasing numbers of older adults with intellectual disabilities are living with ageing parents. These families need support to plan for the future to avoid crisis interventions following parental death. Method: Interviews and focus groups were conducted with people with intellectual disabilities (aged 40+) (N = 9), parents (N = 11) and siblings (N = 16) to understand their perspectives about living with parents and future planning. Data were analysed using framework analysis. Results: Four themes were identified: 'What matters to me', 'When should we plan', 'What are the options' and 'Who will help'. Participants knew they needed to make plans but did not feel supported to do so. While they viewed moving as an opportunity for independence, they feared there were no viable alternatives. Conclusion: Person-centred resources and support are needed for families to plan for transitions in care, including proactive approaches from social services and help to prepare for conversations with social care professionals.

Functional analysis methods allow clinicians to determine the variable(s) that maintain destructive behavior. Previous reviews of functional analysis outcomes have included large samples of published and unpublished data sets (i.e., clinical samples). The purpose of this review was to conduct a large retrospective consecutive controlled case series of clinical functional analyses. We sought to identify the prevalence of differentiation, procedural modifications for undifferentiated and differentiated cases, and identified function(s) of destructive behavior. In addition, we extended the existing literature by determining whether functional analysis differentiation and function varied when single or multiple behavior topographies were consequated in the functional analysis. We discuss our findings considering previously published functional analysis reviews, provide avenues for future research, and offer suggestions for clinical practice.

Societal Impact Statement Human interactions with forests have shaped Earth's climate for millennia and will continue to do so as we target net‐zero emission goals. Accurately characterizing these climate impacts requires making reliable forest carbon data available for forest monitoring and planning. Here, we develop a semi‐automated process for submitting forest carbon measurements from the largest relevant scientific database to the International Panel on Climate Change's Emission Factor Database, which currently has sparse forest carbon data. Building this bridge from scientific research to international policy is an important step towards managing forests in a net‐zero motivated future. Abstract Humans have been influencing Earth's climate via transformative impacts on forests for millennia, and forests are now recognized as critical to climate change mitigation under the Paris Agreement. The efficacy of climate change mitigation planning and reporting depends on quality data on forest carbon (C) stocks and changes. The Emission Factor Database (EFDB) of the International Panel on Climate Change (IPCC) is intended to be a definitive source for such data, but needs comprehensive and well‐documented data to be so. To facilitate submission of forest C estimates from scientific studies to EFDB, we develop and document a process for semi‐automated data submission from the Global Forest C database (ForC v4.0), which is the largest compilation of ground‐based forest C estimates. We then assess the data currently available through ForC and provide recommendations for improving forest data collection, analysis, and reporting. As of September 2024, ForC contained ~19,286 records potentially relevant to EFDB, 1068 of which had been submitted and posted to EFDB. These represented 19% of the total EFDB records for forest land. Records were unevenly distributed across variables and geographic regions. ForC records (37%) reviewed could not be submitted because the original publication lacked required information. In the future, ground‐based forest C estimates should target gaps in the record, and studies should ensure that they report all information necessary for inclusion in EFDB. Given that climate change is rapidly impacting the world's forests, timely reporting of recent estimates will be critical to accurate forest C inventories.

Abstract β-lactam antibiotics have been prescribed for most bacterial infections since their discovery. However, resistance to β-lactams, mediated by β-lactamase (Bla) enzymes such as extended spectrum β-lactamases (ESBLs), has become widespread. Bla inhibitors can restore the efficacy of β-lactams against resistant bacteria, an approach which preserves existing antibiotics despite declining industry investment. However, the effects of combination treatment on selection for β-lactam resistance are not well understood. Bla production confers both private benefits for resistant cells and public benefits which faster-growing sensitive cells can also exploit. These benefits may be differentially impacted by Bla inhibitors, leading to non-intuitive selection dynamics. In this study, we demonstrate strain-to-strain variation in effective combination doses, with complex growth dynamics in mixed populations. Using modeling, we derive a criterion for the selection outcome of combination treatment, dependent on the burden and effective private benefit of Bla production. We then use engineered strains and natural isolates to show that strong private benefits of Bla are associated with increased selection for resistance. Finally, we demonstrate that this parameter can be coarsely estimated using high-throughput phenotyping of clonal populations. Our analysis shows that quantifying the phenotypic responses of bacteria to combination treatment can facilitate resistance-minimizing optimization of treatment.

To tease apart differences between conventional cage (CC) and cage-free (CF) housing systems, this study focuses on the effects of excreta exposure and age by comparing microbial communities, intestinal permeability, and corticosterone in hens in enriched colonies (EC) and CF housing systems during early- and late-lay. Hens were randomly selected from two rooms of CF (n = 20) and EC (n = 20) at 35 and 76 weeks of age. One hour following an oral gavage of fluorescein isothiocyanate dextran (FITC-D), hens were euthanized, and ileal contents and blood were collected. Serum FITC-D using a fluorescent spectrophotometer and corticosterone using a commercial competitive ELISA kit were analyzed. Following DNA isolation from the ileum contents, the V4 region of the 16S rRNA gene was sequenced. Sequence data were filtered in Mothur v1.43.0, followed by de novo operational taxonomic unit (OTU) clustering and classifying with the SILVA SSU v138 reference database. Serum FITC-D was altered by housing type, age of hens, and the interaction between housing type and age of hens (p < 0.001), with 76-week-old hens housed in EC having the highest FITC-D. Corticosterone increased with age (p = 0.023). Microbial community diversity measurements favored hens housed in the CF housing system as ileal contents tended to have increased species evenness (p = 0.008) and greater alpha diversity (p = 0.006). The majority of the over-representation of OTUs were associated with peak lay.

Access to communication is a primary challenge affecting the education of Autistic students who use augmentative and alternative communication devices. This is compounded by potential communication partners (e.g., teachers and classroom paraeducators) who have insufficient training and skills to meaningfully engage these students in communication. To address these deficits in skills and training, this feasibility study used a multiple probe across participants design to test the effects of using behavioral skills training on dyads of teachers and paraeducators in increasing teacher-delivered opportunities to respond and student communication responses. The results show that after training, teachers’ opportunities to respond and use student-specific strategies increased. Following the teachers’ implementation of the strategies, students’ prompted and unprompted communication increased. These results provide evidence that supports the use of behavioral skills training to support communication partner skill development and student communication needs. These methods showed positive social validity with participants and demonstrate a professional development method that is more feasible for use by school staff than individual training. The results of this study provide initial evidence of the effectiveness of these methods with dyads of participants as well as with licensed teachers, extending the extant research, which often focuses on the individual training of paraeducators.

Abstract Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 − 25.8] vs 46.4 [40.6 − 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% − 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants.

Abstract Cardiopulmonary bypass (CPB) can alter pharmacokinetic (PK) parameters and the drug may adsorb to the CPB device, altering exposure. Cefazolin is a beta‐lactam antibiotic used for antimicrobial prophylaxis during cardiac surgery supported by CPB. Adsorption of cefazolin could result in therapeutic failure. An ex vivo study was undertaken using CPB devices primed and then dosed with cefazolin and samples were obtained over 1 hour of recirculation. Twelve experimental runs were conducted using different CPB device sizes (neonate, infant, child, and adult), device coatings (Xcoating™, Rheoparin®, PH.I.S.I.O), and priming solutions. The time course of saturable binding, using Bmax (binding capacity), Kd (dissociation constant), and T2off (half‐time of dissociation), described cefazolin adsorption. Bmax estimates for the device sizes were neonate 40.0 mg (95% CI 24.3, 67.4), infant 48.6 mg (95% CI 5.97, 80.2), child 77.8 mg (95% CI 54.9, 103), and adult 196 mg (95% CI 191, 199). The Xcoating™ Kd estimate was 139 mg/L (95% CI 27.0, 283) and the T2off estimate was 98.4 min (95% CI 66.8, 129). The Rheoparin® and PH.I.S.I.O coatings had similar binding parameters with Kd and T2off estimates of 0.169 mg/L (95% CI 0.01, 1.99) and 4.94 min (95% CI 0.17, 59.4). The Bmax was small (

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

ABSTRACT Salmonella is a common causative agent of infectious intestinal and systemic disease and has been extensively studied for several decades. Yet, much of Salmonella pathogenicity remains a mystery due in part to the highly complex virulence and adaptation strategies at the pathogen’s disposal. One of the more influential tools within the field, an attenuated aroA-deficient Salmonella strain, has been used for many years to probe the host immune response that would otherwise be impossible with a fully virulent strain. Now, new work by Rooke et al. (J. L. Rooke, E. C. A. Goodall, K. Pullela, R. Da Costa, et al., mBio 15:e03319-23, 2024, https://doi.org/10.1128/mbio.03319-23) utilizes in-depth transposon-directed insertion-site sequencing to elucidate the contribution of genes to Salmonella fitness within isogenic wild-type and aroA-deficient strains. Specifically, Rooke et al. demonstrate that the deletion of the aroA gene leads to iron-dependent membrane instability, raising several exciting new ideas surrounding Salmonella biology and therapeutic strategies.

Wetlands are increasingly being constructed to retain phosphorus, but indicators of performance are often unique to individual wetlands. In this quantitative literature synthesis, we highlight two major knowledge gaps and a source of bias in our current understanding of phosphorus retention by constructed and restored wetlands. We performed a literature review to assess differences in wetland characteristics, phosphorus retention, and sampling frequency and duration to better understand how constructed and restored wetlands retain phosphorus. We then examined a series of different sampling frequencies to determine how sampling approaches affect observed trends using a case study at the Old Woman Creek National Estuarine Research Reserve where high-resolution data on phosphorus concentrations was available. We found that, while differences among broad wetland structural groupings exist, measured rates of phosphorus retention are highly variable. Additionally, we observed that the wetlands sampled in the literature are most often newly constructed; 70% of the wetlands were monitored for three or fewer years. Among twelve wetlands that were monitored for over ten years, resampling techniques demonstrated that three-year time scales are unable to predict long-term trends for nutrient retention. Similarly, we found that 70% of wetlands in the literature were sampled weekly or less frequently and did not account for major flow events when estimating nutrient retention. Our case study analysis indicated that excluding storm events lead to a significant underestimate of phosphorus retention. We further demonstrate that when sampling is infrequent and misses storm events, the retention of water and phosphorus by wetlands causes higher underestimates at the inflow than the outflow where phosphorus leaves wetlands more slowly than the inflow. The greater underestimation of loads at outflows compared to inflows can lead to a wetland being mislabeled as a source when it is a sink for phosphorus if storm events are not accounted for. Together this synthesis highlights that our understanding of how constructed wetlands store phosphorus is limited by three major factors: a lack of long-term monitoring, the drivers of high variability in phosphorus retention between different wetland types, and potential bias from the difficulties of capturing storm events. Our analysis indicates that most published works have been conducted at shorter time frames, or lower sampling frequencies than are required for accurate estimates of phosphorus retention. This finding is of significance because substantial investments are made in restoring and constructing wetlands based on inadequately supported assumptions that wetlands are highly effective at phosphorus retention. Ultimately, these results can inform improvements to post-restoration assessment of wetland nutrient function, including decisions on where and when to monitor water quality.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a primary mitochondrial dysfunction affecting mitochondrial fatty acid and protein metabolism, caused by biallelic pathogenic variants in ETFA, ETFB, or ETFDH genes. The heterogeneous phenotypes associated with MADD have been classified into three groups: neonatal onset with congenital anomalies (type 1), neonatal onset without congenital anomalies (type 2), and attenuated and/or later onset (type 3). Here, we present two cases with biochemical profiles mimicking late-onset MADD but negative genetic testing, associated with the use of sertraline, a commonly used antidepressant. Case 1 is a 22 yo woman diagnosed with depression and profound fatigue who was referred to the metabolic clinic because of carnitine deficiency and a plasma acylcarnitine profile with a MADD-like pattern. Case 2 is a 61 yo woman with a history of chronic fatigue who was admitted to the emergency department with difficulty swallowing, metabolic acidosis, and mild rhabdomyolysis. Plasma acylcarnitine profile showed a MADD-like pattern. The muscle biopsy revealed lipid droplet accumulation and proliferation of mitochondria with abnormal osmiophilic inclusions, and a biochemical assay of the respiratory chain showed a deficit in complex II activity. In both cases, urine organic acid profile was normal, and genetic tests did not detect variants in the genes involved in MADD. Sertraline was on their list of medications and considering its association with inhibition of mitochondrial function and rhabdomyolysis, the team recommended the discontinuation under medical supervision. In Case 1 after discontinuation, the plasma acylcarnitine test normalized, only to return abnormal when the patient resumed sertraline. In Case 2, after sertraline was discontinued rhabdomyolysis resolved, and the muscle biopsy and biochemical assay of the respiratory chain normalized. Although sertraline is considered a safe drug, these two cases suggest that the use of sertraline may be associated with a potentially reversible form of mitochondrial dysfunction mimicking MADD. Further studies are needed to confirm and estimate the risk of MADD-like presentations with the use of sertraline, as well as identifying additional contributing factors, including genetic factors. Metabolic physicians should consider sertraline use in the differential diagnosis of MADD, particularly when genetic testing is negative.

ABSTRACTEmerging SARS-CoV-2 sublineages continue to cause serious COVID-19 disease, but most individuals have not received any COVID-19 vaccine for >1 year. Assessment of long-term effectiveness of bivalent COVID-19 vaccines against circulating sublineages is important to inform the potential need for vaccination with updated vaccines. In this test-negative study at Kaiser Permanente Southern California, sequencing-confirmed BA.4/BA.5- or XBB-related SARS-CoV-2-positive cases (September 1, 2022 to June 30, 2023), were matched 1:3 to SARS-CoV-2-negative controls. We assessed mRNA-1273 bivalent relative (rVE) and absolute vaccine effectiveness (VE) compared to ≥2 or 0 doses of original monovalent vaccine, respectively. The rVE analysis included 20,966 cases and 62,898 controls. rVE (95%CI) against BA.4/BA.5 at 14–60 days and 121–180 days was 52.7% (46.9–57.8%) and 35.5% (−2.8–59.5%) for infection, and 59.3% (49.7–67.0%) and 33.2% (−28.2–68.0%) for Emergency Department/Urgent Care (ED/UC) encounters. For BA.4/BA.5-related hospitalizations, rVE was 71.3% (44.9–85.1%) and 52.0% (−1.2–77.3%) at 14–60 days and 61–120 days, respectively. rVE against XBB at 14–60 days and 121–180 days was 48.8% (33.4–60.7%) and −3.9% (−18.1–11.3%) for infection, 70.7% (52.4–82.0%) and 15.7% (−6.0–33.2%) for ED/UC encounters, and 87.9% (43.8–97.4%) and 57.1% (17.0–77.8%) for hospitalization. VE and subgroup analyses (age, immunocompromised status, previous SARS-CoV-2 infection) results were similar to rVE analyses. rVE of mRNA-1273 bivalent vaccine against BA.4/BA.5 and XBB infections, ED/UC encounters, and hospitalizations waned over time. Periodic revaccination with vaccines targeting emerging variants may be important in reducing COVID-19 morbidity and mortality.

It has been suggested that caricaturing enhances esthetic appeal, by making an image more strongly stimulate those areas of the brain encoding the subject's distinctive features than does the subject itself. However, some experimental work suggests that people prefer faces with proportions closer to average, or closer to a particular template. It might be that familiarity with the face is important if caricaturing is to increase the esthetic appeal of a likeness. Here we examined how automated caricaturing of photographs of nominal celebrities influenced judgments of esthetic appeal, and how familiarity with the celebrities affected these. Caricaturing monotonically decreased the esthetic appeal of the celebrity photographs, with subjects’ familiarity with the celebrity not influencing this relationship. The degree to which caricaturing influenced esthetic appeal was not correlated with judgments of relative spatial dimensions for a simple shape, either in a discrimination threshold experiment or a peak-shift experiment.

Monitoring neuronal activity at single-cell resolution in freely moving Drosophila engaged in social behaviors is challenging because of their small size and lack of transparency. Extant methods, such as Flyception, are highly invasive. Whole-brain calcium imaging in head-fixed, walking flies is feasible but the animals cannot perform the consummatory phases of social behaviors like aggression or mating under these conditions. This has left open the fundamental question of whether neurons identified as functionally important for such behaviors using loss- or gain-of-function screens are actually active during the natural performance of such behaviors, and if so during which phase(s). Here, we perform brain-wide mapping of active cells expressing the Immediate Early Gene hr38 using a high-sensitivity/low background fluorescence in situ hybridization (FISH) amplification method called HCR-3.0. Using double-labeling for hr38 mRNA and for GFP, we describe the activity of several classes of aggression-promoting neurons during courtship and aggression, including P1a cells, an intensively studied population of male-specific interneurons. Using HI-FISH in combination with optogenetic activation of aggression-promoting neurons (opto-HI-FISH), we identify candidate downstream functional targets of these cells in a brain-wide, unbiased manner. Finally, we compare the activity of P1a neurons during sequential performance of courtship and aggression, using intronic vs. exonic hr38 probes to differentiate newly synthesized nuclear transcripts from cytoplasmic transcripts synthesized at an earlier time. These data provide evidence suggesting that different subsets of P1a neurons may be active during courtship vs. aggression. HI-FISH and associated methods may help to fill an important lacuna in the armamentarium of tools for neural circuit analysis in Drosophila.

To transform continuous speech into words, the human brain must resolve variability across utterances in intonation, speech rate, volume, accents and so on. A promising approach to explaining this process has been to model electroencephalogram (EEG) recordings of brain responses to speech. Contemporary models typically invoke context invariant speech categories (e.g. phonemes) as an intermediary representational stage between sounds and words. However, such models may not capture the complete picture because they do not model the brain mechanism that categorizes sounds and consequently may overlook associated neural representations. By providing end-to-end accounts of speech-to-text transformation, new deep-learning systems could enable more complete brain models. We model EEG recordings of audiobook comprehension with the deep-learning speech recognition system Whisper. We find that (1) Whisper provides a self-contained EEG model of an intermediary representational stage that reflects elements of prelexical and lexical representation and prediction; (2) EEG modeling is more accurate when informed by 5-10s of speech context, which traditional context invariant categorical models do not encode; (3) Deep Whisper layers encoding linguistic structure were more accurate EEG models of selectively attended speech in two-speaker "cocktail party" listening conditions than early layers encoding acoustics. No such layer depth advantage was observed for unattended speech, consistent with a more superficial level of linguistic processing in the brain.

AimTo explore parents’ experiences of using continuous glucose monitoring (CGM) in their young children with early-stage type 1 diabetes, being followed in the Australian Environmental Determinants of Islet Autoimmunity (ENDIA) study.MethodsParents of children with persistent islet autoimmunity who enrolled in the ENDIA CGM sub-study were invited to participate in an optional interview. Semi-structured phone interviews were conducted by a single researcher using an interview guide developed by a multi-disciplinary team. Interviews were conducted following a single CGM monitoring period and prior to parents receiving feedback on their child’s glycemic status. Following transcription, thematic analysis was conducted to determine common themes.ResultsNine parents (8 mothers, 1 father) were interviewed corresponding to ten children, with a mean (SD) age of 5.6 (2.2) years, who wore CGM for 97 (0.1)% of the time during their monitoring period. Three main themes were identified: (1) Information empowers and helps to reduce uncertainty; (2) Families’ acceptance of using CGM; and (3) Involvement in research provides support and preparation for the unknown.ConclusionsParents reported a positive experience of their young child wearing blinded CGM, and the children tolerated wearing CGM very well. Parents were empowered by knowing they would receive information on their child’s glucose levels and patterns and felt well supported. This study provides novel insights into parents’ experiences of using CGM in very young children with early-stage type 1 diabetes.

BackgroundA wide range of household secondary infection rates has been reported, and the role of children in population transmission dynamics for SARS-CoV-2 remains ill-defined. We sought to better understand household infection early in the pandemic.MethodologyA cross-sectional study of 17 households in the Atlanta metropolitan area with at least one child and one case of COVID-19 in the prior 1–4 months were recruited between December 2020 and April 2021. Self-collected saliva samples were tested on a multiplexed platform to detect IgG antibodies that bind to SARS-CoV-2 antigens. Secondary infection rates (SIR) were calculated and compared.ResultsWe report results on 17 families, including 66 individuals. We found an average SIR of 0.58; children and adults were similarly infected (62% children vs. 75% adults) (p = 0.2). Two out of 17 households had a pediatric index per our definition. Number of pediatric infections per household (p = 0.18), isolation (p = 0.34), and mask wearing (p = 0.80) did not differ significantly among households with an SIR above the mean vs. those with SIR below the mean. Households with higher SIR also had a higher number of symptomatic cases (p

The Arctic is warming at a faster rate compared to the globe on average, a phenomenon commonly referred to as Arctic amplification. Sea ice has been linked to Arctic amplification and has gathered attention recently due to the decline in summer sea ice extent. Data assimilation (DA) is the act of combining observations with prior forecasts to obtain a more accurate model state. Sea ice poses a unique challenge for DA because sea ice variables have bounded distributions, leading to non-Gaussian distributions. The non-Gaussian nature violates the Gaussian assumptions built into DA algorithms. This study presents different observing system simulation experiments (OSSEs), which will provide a data assimilating testing framework through experimental observation networks and synthetic observations. The OSSE framework will help determine the best data assimilation configuration for assimilating sea ice and snow observations. Findings indicate that assimilating both sea ice thickness and snow depth observations while omitting sea ice concentration observations produced the best sea ice and snow forecasts in our idealized experimental setup. A simplified DA experiment helped demonstrate that the DA solution is biased when assimilating sea ice concentration observations. The biased DA solution is related to the observation error distribution being a truncated normal distribution, and the assumed observation likelihood is normal for the DA method. Additional OSSEs show that using a non-Gaussian DA method does not alleviate the non-Gaussian effects of sea ice concentration observations, and assimilating sea ice surface temperatures has a positive impact on snow updates. Finally, it is shown that the perturbed sea ice model parameters used to create additional ensemble spread in the free forecasts lead to a year-long negative snow volume bias.

Abstract The southern coast of Africa is one of the few places in the world where water temperatures are predicted to cool in the future. This endemism-rich coastline is home to two sister species of kelps of the genus Ecklonia maxima and Ecklonia radiata, each associated with specific thermal niches, and occuring primarily on opposite sides of the southern tip of Africa. Historical distribution records indicate that E. maxima has recently shifted its distribution ~ 70 km eastward, to sites where only E. radiata was previously reported. The contact of sister species with contrasting thermal affinities and the occurrence of mixed morphologies raised the hypothesis that hybridization might be occurring in this contact zone. Here we describe the genetic structure of the genus Ecklonia along the southern coast of Africa and investigate potential hybridization and cryptic diversity using a combination of nuclear microsatellites and mitochondrial markers. We found that both species have geographically discrete genetic clusters, consistent with expected phylogeographic breaks along this coastline. In addition, depth-isolated populations were found to harbor unique genetic diversity, including a third Ecklonia lineage. Mito-nuclear discordance and high genetic divergence in the contact zones suggest multiple hybridization events between Ecklonia species. Discordance between morphological and molecular identification suggests the potential influence of abiotic factors leading to convergent phenotypes in the contact zones. Our results highlight an example of cryptic diversity and hybridization driven by contact between two closely related keystone species with contrasting thermal affinities.

Abstract Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Abstract Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

Streamflow elasticity is the ratio of the expected percentage change in streamflow to a 1 % change in precipitation – a simple approximation of how responsive a river is to precipitation. Typically, streamflow elasticity is estimated for average annual streamflow; however, we propose a new concept in which streamflow elasticity is estimated for multiple percentiles across the full distribution of streamflow. This “elasticity curve” can then be used to develop a more complete depiction of how streamflow responds to climate. Representing elasticity as a curve which reflects the range of responses across the distribution of streamflow within a given time period, instead of as a single-point estimate, provides a novel lens through which we can interpret hydrological behaviour. As an example, we calculate elasticity curves for 805 catchments in the United States and then cluster them according to their shape. This results in three distinct elasticity curve types which characterize the streamflow–precipitation relationship at annual and seasonal timescales. Through this, we demonstrate that elasticity estimated from the central summary of streamflow, e.g. the annual median, does not provide a complete picture of streamflow sensitivity. Further, we show that elasticity curve shape, i.e. the response of different flow percentiles relative to one another in one catchment, can be interpreted separately from between-catchment variation in the average magnitude of streamflow change associated with a 1 % change in precipitation. Finally, we find that available water storage is likely the key control which determines curve shape.

The Measurements Of Pollution In The Troposphere (MOPITT) is an ideal instrument to understand the impact of (1) assimilating multispectral and joint retrievals versus single spectral products, (2) assimilating satellite profile products versus column products, and (3) assimilating multispectral and joint retrievals versus assimilating individual products separately. We use the Community Atmosphere Model with chemistry with the Data Assimilation Research Testbed (CAM-chem+DART) to assimilate different MOPITT carbon monoxide (CO) products to address these three questions. Both anthropogenic and fire CO emissions are optimized in the data assimilation experiments. The results are compared with independent CO observations from TROPOspheric Monitoring Instrument (TROPOMI), the Total Carbon Column Observing Network (TCCON), NOAA Carbon Cycle Greenhouse Gases (CCGG) sites, In-service Aircraft for a Global Observing System (IAGOS), and Western wildfire Experiment for Cloud chemistry, Aerosol absorption and Nitrogen (WE-CAN). We find that (1) assimilating the MOPITT joint (multispectral; near-IR and thermal IR) column product leads to better model–observation agreement at and near the surface than assimilating the MOPITT thermal-IR-only column retrieval. (2) Assimilating column products has a larger impact and improvement for background and large-scale CO compared to assimilating profile products due to vertical localization in profile assimilation. However, profile assimilation can outperform column assimilations in fire-impacted regions and near the surface. (3) Assimilating multispectral and joint products results in similar or slightly better agreement with observations compared to assimilating the single spectral products separately.

Summary: Runt-related transcription factor 1 translocated to 1 (RUNX1T1; also known as eight-twenty-one [ETO]) encodes a transcription regulator for hematopoietic genes and is well known for its involvement in hematologic malignancies, particularly acute myeloid leukemia (AML). However, its role in congenital disease is less understood. This study provides detailed clinical and molecular information on three cases exhibiting neurodevelopmental and congenital anomalies with germline de novo alterations in RUNX1T1. One case features a de novo nonsense variant in the 5′ region of the gene (c.106C>T p.Gln36Ter), while the other two harbor de novo missense variants in the C terminus end (c.1234G>A p.Gly412Arg and c.1561C>T p.His521Tyr). Common features across cases include craniofacial dysmorphism and neurodevelopmental issues, including developmental delay, learning disabilities, attention-deficit hyperactivity disorder, and autism. This study, in conjunction with previously reported germline disruptions of RUNX1T1, provides evidence supporting the role of germline RUNX1T1 variation in human congenital neurodevelopmental disorders.

Purpose: To investigate subconjunctival administration of a single-stranded, adeno-associated virus, serotype 2, engineered to express stanniocalcin-1 with a FLAG tag (ssAAV2-STC-1-FLAG) as a novel sustained (IOP) lowering agent with a reduced ocular surface side effect profile. Design: In vivo preclinical investigation in mice. Subjects: C57BL/6J, DBA/2J, prostaglandin F (FP) receptor knockout mice. Methods: Normotensive C57BL/6J mice were treated with a subconjunctival injection of ssAAV2-STC-1-FLAG (2 μL; 6 × 109 viral genomes [VGs]) in 1 eye and the same volume and concentration of ssAAV2-green fluorescent protein (GFP) or the same volume of phosphate-buffered saline in the fellow eye. Ocular hypertensive DBA/2J mice were subconjunctivally injected with 6 × 109 VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Steroid-mediated ocular hypertension was induced in C57BL/6J mice with weekly injections of dexamethasone into the conjunctival fornix, and mice were then injected subconjunctivally with 6 × 109 VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Prostaglandin F receptor knockout mice were injected subconjunctivally with 6 × 109 VGs of ssAAV2-STC-1-FLAG or phosphate-buffered saline. An identical vector was constructed without the FLAG tag (ssAAV2-STC-1) and evaluated in normotensive C57BL/6J mice. Intraocular pressure was assessed using the Tonolab tonometer for all experiments. Tumor necrosis factor alpha (TNFα), a marker of ocular surface inflammation, was compared between subconjunctivally delivered ssAAV2-STC-1-FLAG and other treatments including daily topical latanoprost. Main Outcome Measures: Intraocular pressure assessment. Results: Subconjunctival delivery of ssAAV2-STC-1-FLAG significantly reduced IOP for 10 weeks post injection in normotensive mice. Maximal IOP reduction was seen at week 3 postinjection (17.4%; 17.1 ± 0.8 vs. 14.1 ± 0.8 mmHg, P

Achromatopsia is an inherited retinal disease that affects 1 in 30,000–50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.

In this study, a detailed metric survey on the “Galaxy 15” (April 2010) space weather event is conducted to validate MAGNetosphere–Ionosphere–Thermosphere (MAGNIT), a semi-physical auroral ionospheric conductance model characterizing four precipitation sources, against AMPERE measurements via field-aligned current (FAC) characteristics. As part of this study, the comparative performance of three ionosphere electrodynamic specifications involving auroral conductance models, MAGNIT, Ridley Legacy Model (RLM) (empirical), and Conductance Model for Extreme Events (CMEE) (empirical), within the Space Weather Modeling Framework (SWMF), is demonstrated. Overall, MAGNIT exhibits marginally improved predictions; root mean square error values in upward and downward FACs of MAGNIT predictions compared to AMPERE data are smaller than those of CMEE and Ridley Ionosphere Model (RIM) by ∼12.7% and ∼6.24% before the storm, ∼4.52% and ∼2.13% better during the main phase, ∼1.98% and ∼1.27% worse during the second minimum, and better by ∼1.84% and ∼1.49% by the beginning of the recovery, respectively. In all three model configurations, the dusk and night magnetic local time (MLT) sectors over-predict throughout the storm, while the day and dawn MLT sectors under-predict in response to interplanetary magnetic field (IMF) conditions. In addition to accuracy and bias, similar results and conclusions are drawn from additional metrics, including in the categories of correlation, precision, extremes, and skill, and recommendations are made for the best-performing model configuration in each metric category. Visual data–model comparisons conducted by studying the FAC location and latitude/MLT spread throughout various phases of the storm suggest that the spatial extent of the FACs is captured relatively well in the night-side auroral oval, unlike in the day-side oval. The spread in latitude of the FACs matches that in the previous literature on other model performances. This information on auroral precipitation sources and their weight on FACs, along with metrics from model–data comparisons, can be used to modify MAGNIT settings to optimize SWMF model performance.

Abstract Coproduction represents an inclusive approach for developing decision‐support resources because it seeks to integrate scientific knowledge and end‐user needs. Unfortunately, spatial decision support systems (SDSS) coproduction has sometimes resulted in limited utility for end‐users, partially due to scarce SDSS coproduction guidance. To initiate coproduction, we held a series of workshops to co‐design a spatial conservation prioritization tool for sagebrush ecosystems in the western United States. We share four themes derived from participant feedback and our reflections to guide future SDSS codesign efforts. We found end‐user confidence in data inputs and transparency regarding SDSS assumptions generated trust. Workshop participants noted our virtual format, with smaller break‐out groups, effectively facilitated discussions. Ultimately, end‐users appreciated the conservation context provided by regional‐scale SDSS but preferred local‐scale prioritization efforts for site‐level planning. Therefore, we are shifting ongoing co‐design efforts to consider local‐scale tool development, which can scale up to larger geographic extents.

Abstract Semiconductor wafer manufacturing relies on the precise control of various performance metrics to ensure the quality and reliability of integrated circuits. In particular, GaN has properties that are advantageous for high voltage and high frequency power devices; however, defects in the substrate growth and manufacturing are preventing vertical devices from performing optimally. This paper explores the application of machine learning techniques utilizing data obtained from optical profilometry as input variables to predict the probability of a wafer meeting performance metrics, specifically the breakdown voltage (Vbk). By incorporating machine learning techniques, it is possible to reliably predict performance metrics that cause devices to fail at low voltage. For diodes that fail at a higher (but still below theoretical) breakdown voltage, alternative inspection methods or a combination of several experimental techniques may be necessary.

Abstract Evidence is strong for adverse fetal effects of high level or chronic prenatal alcohol exposure (PAE), but many pregnant women continue to drink at lower levels. The ‘Asking Questions about Alcohol in pregnancy’ prospective cohort aimed to determine the neurodevelopmental consequences at 6–8 years of age of low to moderate PAE. 1570 women from seven public antenatal clinics in Melbourne, Australia, provided information on frequency and quantity of alcohol use, and obstetric, lifestyle and socio-environmental confounders at four gestation timepoints. PAE was classified into five trajectories plus controls. At 6–8 years, 802 of 1342 eligible families took part and completed a questionnaire (60%) and 696 children completed neuropsychological assessments (52%). Multiple linear regressions examined mean outcome differences between groups using complete case and multiple imputation models. No meaningful relationships were found between any of the PAE trajectories and general cognition, academic skills, motor functioning, behaviour, social skills, social communication, and executive function. Maternal education most strongly influenced general cognition and academic skills. Parenting behaviours and financial situation were associated with academic skills, behaviour, social skills and/or executive function. The lack of association between PAE and neurodevelopment at 6–8 years may partly be explained by cumulative positive effects of socio-environmental factors.

Abstract Regeneration in the injured spinal cord is limited by physical and chemical barriers. Acute implantation of a multichannel poly(lactide-co-glycolide) (PLG) bridge mechanically stabilizes the injury, modulates inflammation, and provides a permissive environment for rapid cellularization and robust axonal regrowth through this otherwise inhibitory milieu. However, without additional intervention, regenerated axons remain largely unmyelinated (